(Aryloxy)alkylamines as selective human dopamine D4 receptor antagonists: potential antipsychotic agents.

The discovery of a series of novel (aryloxy)alkylamines with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. A number of compounds demonstrated subnanomolar Ki values for binding to the D4 receptor, with several 100-fold selectivities toward the D2 and D3 receptors. Several compounds with combined D3/D4 receptor binding selectivity were also identified. A limited structure-activity relationship study of this chemical series is discussed. In a mitogenesis functional assay, the effect of the test compounds on cellular uptake of [3H]thymidine in D4-transfected CHO 10,001 cells was measured and compared to the response of the full dopamine agonist quinpirole. The activity of the compounds varied from full antagonist to weak partial agonist activity (intrinsic activity of 0-19% in comparison to quinpirole).

Chromeno[3,4-c]pyridin-5-ones: selective human dopamine D4 receptor antagonists as potential antipsychotic agents.

The discovery of a series of chromeno[3,4-c]pyridin-5-ones with selective affinity for the dopamine D4 receptor is described. Target compounds were tested for binding to cloned human dopamine D2, D3, and D4 receptor subtypes expressed in Chinese hamster ovary (CHO) K-1 cells. Several compounds demonstrated single digit nanomolar Ki values for binding to the D4 receptor with several hundred-fold selectivities toward the D2 and D3 receptors. A limited SAR study of this series is discussed. In a mitogenesis assay measuring [3H]thymidine uptake, the target compounds showed antagonist to weak partial agonist activity at the D4 receptor, with intrinsic activities ranging from 0 to 35%. Compound 6, 3-benzyl-8-methyl-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, increased DOPA (L-3,4-dihydroxyphenylalanine) synthesis 84% in the hippocampus and 10% in the striatum of rat brain when dosed orally at 10 mg/kg.

8-Amino-9-substituted guanines: potent purine nucleoside phosphorylase (PNP) inhibitors.

A series of 8-amino-9-substituted guanines was synthesized and their activity evaluated against human purine nucleoside phosphorylase (PNP). All compounds were found to be potent inhibitors of human PNP (IC50s: 0.17-126 microM). They were also selectively cytotoxic to MOLT-4 lymphoblasts in the presence of a nontoxic amount (10 microM) of the PNP substrate, 2'-deoxyguanosine (GdR). The most potent of these analogs, 2,8-diamino-1,9-dihydro-9-(2-thienylmethyl)-6H-purin-6-one (8-amino-9-(2-thienylmethyl)guanine; PD 119,229) has an IC50 of 0.17 microM (Ki = 0.067 microM), significantly more potent than the known standard, 8-aminoguanosine (IC50 = 1.40 microM). Thus it represents the most potent PNP inhibitor known to date when tested without limiting the concentration of inorganic phosphate.

Hydroxylamine analogs of 2,6-di-t-butylphenols: dual inhibitors of cyclooxygenase and 5-lipoxygenase or selective 5-lipoxygenase inhibitors.

The preparation of hydroxylamine analogs of 2,6-di-tert-butylphenols (DTBP) and the inhibition of cyclooxygenase (CO) and 5-lipoxygenase (5-LO) by these compounds is discussed.

Pyrazolo[1,5-a]pyrimidine CRF-1 receptor antagonists.

A series of 3-phenylpyrazolo[1,5-a]pyrimidines was prepared and found to have affinity for the human CRF-1 receptor. The 3-dimensional structure of one of the most potent analogs in this series, 10d, was determined by X-ray crystallography and suggests the spatial requirements for potent CRF-1 receptor binding affinity in this series.